A fully synthetic three-dimensional human cerebrovascular model based on histological characteristics to investigate the hemodynamic fingerprint of the layer BOLD fMRI signal formation.

Recent advances in functional magnetic resonance imaging (fMRI) at ultra-high field (≥7 tesla), novel hardware, and data analysis methods have enabled detailed research on neurovascular function, such as cortical layer-specific activity, in both human and nonhuman species. A widely used fMRI technique relies on the blood oxygen level-dependent (BOLD) signal. BOLD fMRI offers insights into brain function by measuring local changes in cerebral blood volume, cerebral blood flow, and oxygen metabolism induced by increased neuronal activity. Despite its potential, interpreting BOLD fMRI data is challenging as it is only an indirect measurement of neuronal activity. Computational modeling can help interpret BOLD data by simulating the BOLD signal formation. Current developments have focused on realistic 3D vascular models based on rodent data to understand the spatial and temporal BOLD characteristics. While such rodent-based vascular models highlight the impact of the angioarchitecture on the BOLD signal amplitude, anatomical differences between the rodent and human vasculature necessitate the development of human-specific models. Therefore, a computational framework integrating human cortical vasculature, hemodynamic changes, and biophysical properties is essential. Here, we present a novel computational approach: a three-dimensional VAscular MOdel based on Statistics (3D VAMOS), enabling the investigation of the hemodynamic fingerprint of the BOLD signal within a model encompassing a fully synthetic human 3D cortical vasculature and hemodynamics. Our algorithm generates microvascular and macrovascular architectures based on morphological and topological features from the literature on human cortical vasculature. By simulating specific oxygen saturation states and biophysical interactions, our framework characterizes the intravascular and extravascular signal contributions across cortical depth and voxel-wise levels for gradient-echo and spin-echo readouts. Thereby, the 3D VAMOS computational framework demonstrates that using human characteristics significantly affects the BOLD fingerprint, making it an essential step in understanding the fundamental underpinnings of layer-specific fMRI experiments.

The many layers of BOLD. The effect of hypercapnic and hyperoxic stimuli on macro- and micro-vascular compartments quantified by CVR, M, and CBV across cortical depth.

Ultra-high field functional magnetic resonance imaging (fMRI) offers the spatial resolution to measure neuronal activity at the scale of cortical layers. However, cortical depth dependent vascularization differences, such as a higher prevalence of macro-vascular compartments near the pial surface, have a confounding effect on depth-resolved blood-oxygen-level dependent (BOLD) fMRI signals. In the current study, we use hypercapnic and hyperoxic breathing conditions to quantify the influence of all venous vascular and micro-vascular compartments on laminar BOLD fMRI, as measured with gradient-echo (GE) and spin-echo (SE) scan sequences, respectively. We find that all venous vascular and micro-vascular compartments are capable of comparable theoretical maximum signal intensities, as represented by the M-value parameter. However, the capacity for vessel dilation, as reflected by the cerebrovascular reactivity (CVR), is approximately two and a half times larger for all venous vascular compartments combined compared to the micro-vasculature at superficial layers. Finally, there is roughly a 35% difference in estimates of CBV changes between all venous vascular and micro-vascular compartments, although this relative difference was approximately uniform across cortical depth. Thus, our results suggest that fMRI BOLD signal differences across cortical depth are likely caused by differences in dilation properties between macro- and micro-vascular compartments.

Moving in on human motor cortex. Characterizing the relationship between body parts with non-rigid population response fields.

For cortical motor activity, the relationships between different body part representations is unknown. Through reciprocal body part relationships, functionality of cortical motor areas with respect to whole body motor control can be characterized. In the current study, we investigate the relationship between body part representations within individual neuronal populations in motor cortices, following a 7 Tesla fMRI 18-body-part motor experiment in combination with our newly developed non-rigid population Response Field (pRF) model and graph theory. The non-rigid pRF metrics reveal somatotopic structures in all included motor cortices covering frontal, parietal, medial and insular cortices and that neuronal populations in primary sensorimotor cortex respond to fewer body parts than secondary motor cortices. Reciprocal body part relationships are estimated in terms of uniqueness, clique-formation, and influence. We report unique response profiles for the knee, a clique of body parts surrounding the ring finger, and a central role for the shoulder and wrist. These results reveal associations among body parts from the perspective of the central nervous system, while being in agreement with intuitive notions of body part usage.

Intracortical Somatosensory Stimulation to Elicit Fingertip Sensations in an Individual With Spinal Cord Injury.

BACKGROUND AND OBJECTIVES: The restoration of touch to fingers and fingertips is critical to achieving dexterous neuroprosthetic control for individuals with sensorimotor dysfunction. However, localized fingertip sensations have not been evoked via intracortical microstimulation (ICMS). METHODS: Using a novel intraoperative mapping approach, we implanted electrode arrays in the finger areas of left and right somatosensory cortex and delivered ICMS over a 2-year period in a human participant with spinal cord injury. RESULTS: Stimulation evoked tactile sensations in 8 fingers, including fingertips, spanning both hands. Evoked percepts followed expected somatotopic arrangements. The subject was able to reliably identify up to 7 finger-specific sites spanning both hands in a finger discrimination task. The size of the evoked percepts was on average 33% larger than a finger pad, as assessed via manual markings of a hand image. The size of the evoked percepts increased modestly with increased stimulation intensity, growing 21% as pulse amplitude increased from 20 to 80 µA. Detection thresholds were estimated on a subset of electrodes, with estimates of 9.2 to 35 µA observed, roughly consistent with prior studies. DISCUSSION: These results suggest that ICMS can enable the delivery of consistent and localized fingertip sensations during object manipulation by neuroprostheses for individuals with somatosensory deficits. CLINICALTRIALSGOV IDENTIFIER: NCT03161067.

Novel intraoperative online functional mapping of somatosensory finger representations for targeted stimulating electrode placement: technical note.

Defining eloquent cortex intraoperatively, traditionally performed by neurosurgeons to preserve patient function, can now help target electrode implantation for restoring function. Brain-machine interfaces (BMIs) have the potential to restore upper-limb motor control to paralyzed patients but require accurate placement of recording and stimulating electrodes to enable functional control of a prosthetic limb. Beyond motor decoding from recording arrays, precise placement of stimulating electrodes in cortical areas associated with finger and fingertip sensations allows for the delivery of sensory feedback that could improve dexterous control of prosthetic hands. In this study, the authors demonstrated the use of a novel intraoperative online functional mapping (OFM) technique with high-density electrocorticography to localize finger representations in human primary somatosensory cortex. In conjunction with traditional pre- and intraoperative targeting approaches, this technique enabled accurate implantation of stimulating microelectrodes, which was confirmed by postimplantation intracortical stimulation of finger and fingertip sensations. This work demonstrates the utility of intraoperative OFM and will inform future studies of closed-loop BMIs in humans.

A Novel 2D Standard Cartesian Representation for the Human Sensorimotor Cortex.

For some experimental approaches in brain imaging, the existing normalization techniques are not always sufficient. This may be the case if the anatomical shape of the region of interest varies substantially across subjects, or if one needs to compare the left and right hemisphere in the same subject. Here we propose a new standard representation, building upon existing normalization methods: Cgrid (Cartesian geometric representation with isometric dimensions). Cgrid is based on imposing a Cartesian grid over a cortical region of interest that is bounded by anatomical (atlas-based) landmarks. We applied this new representation to the sensorimotor cortex and we evaluated its performance by studying the similarity of activation patterns for hand, foot and tongue movements between subjects, and similarity between hemispheres within subjects. The Cgrid similarities were benchmarked against the similarities of activation patterns when transformed into standard MNI space using SPM, and to similarities from FreeSurfer's surface-based normalization. For both between-subject and between-hemisphere comparisons, similarity scores in Cgrid were high, similar to those from FreeSurfer normalization and higher than similarity scores from SPM's MNI normalization. This indicates that Cgrid allows for a straightforward way of representing and comparing sensorimotor activity patterns across subjects and between hemispheres of the same subjects.

Detailed somatotopy in primary motor and somatosensory cortex revealed by Gaussian population receptive fields.

The relevance of human primary motor cortex (M1) for motor actions has long been established. However, it is still unknown how motor actions are represented, and whether M1 contains an ordered somatotopy at the mesoscopic level. In the current study we show that a detailed within-limb somatotopy can be obtained in M1 during finger movements using Gaussian population Receptive Field (pRF) models. Similar organizations were also obtained for primary somatosensory cortex (S1), showing that individual finger representations are interconnected throughout sensorimotor cortex. The current study additionally estimates receptive field sizes of neuronal populations, showing differences between finger digit representations, between M1 and S1, and additionally between finger digit flexion and extension. Using the Gaussian pRF approach, the detailed somatotopic organization of M1 can be obtained including underlying characteristics, allowing for the in-depth investigation of cortical motor representation and sensorimotor integration.

Knowing left from right: asymmetric functional connectivity during resting state.

The functional organization of left and right hemispheres is different, and hemispheric asymmetries are thought to underlie variations in brain function across individuals. In this study, we assess how differences between hemispheres are reflected in Asymmetric Functional Connectivity (AFC), which provides a full description of how the brain's connectivity structure during resting state differs from that of the same brain mirrored over the longitudinal fissure. In addition, we assess how AFC varies across subjects. Data were provided by the Human Connectome Project, including 423 resting state and combined language task fMRI data sets, and the pattern of AFC was established for all subjects. While we could quantify the symmetry of brain connectivity at 95%, significant asymmetries were observed, consisting foremost of: (1) higher correlations between language areas in the left hemisphere than between their right hemisphere homologues. (2) Higher correlations between language homologue areas in the right hemisphere and left default mode network, than between language areas in the left hemisphere and the default mode network in the right hemisphere. The extent to which subjects exhibited this pattern correlated with language lateralization and handedness. Further exploration in intersubject variation in AFC revealed several additional patterns, one involving entire hemispheres, and another correlations with limbic areas. These results show that language is an important, but not only determinant of AFC. The additional patterns of AFC require further research to be linked to specific asymmetric neuronal states or events.

Predictive coding for motion stimuli in human early visual cortex.

The current study investigates if early visual cortical areas, V1, V2 and V3, use predictive coding to process motion information. Previous studies have reported biased visual motion responses at locations where novel visual information was presented (i.e., the motion trailing edge), which is plausibly linked to the predictability of visual input. Using high-field functional magnetic resonance imaging (fMRI), we measured brain activation during predictable versus unpreceded motion-induced contrast changes during several motion stimuli. We found that unpreceded moving dots appearing at the trailing edge gave rise to enhanced BOLD responses, whereas predictable moving dots at the leading edge resulted in suppressed BOLD responses. Furthermore, we excluded biases in directional sensitivity, shifts in cortical stimulus representation, visuo-spatial attention and classical receptive field effects as viable alternative explanations. The results clearly indicate the presence of predictive coding mechanisms in early visual cortex for visual motion processing, underlying the construction of stable percepts out of highly dynamic visual input.

Patterns of resting state connectivity in human primary visual cortical areas: a 7T fMRI study.

The nature and origin of fMRI resting state fluctuations and connectivity are still not fully known. More detailed knowledge on the relationship between resting state patterns and brain function may help to elucidate this matter. We therefore performed an in depth study of how resting state fluctuations map to the well known architecture of the visual system. We investigated resting state connectivity at both a fine and large scale within and across visual areas V1, V2 and V3 in ten human subjects using a 7Tesla scanner. We found evidence for several coexisting and overlapping connectivity structures at different spatial scales. At the fine-scale level we found enhanced connectivity between the same topographic locations in the fieldmaps of V1, V2 and V3, enhanced connectivity to the contralateral functional homologue, and to a lesser extent enhanced connectivity between iso-eccentric locations within the same visual area. However, by far the largest proportion of the resting state fluctuations occurred within large-scale bilateral networks. These large-scale networks mapped to some extent onto the architecture of the visual system and could thereby obscure fine-scale connectivity. In fact, most of the fine-scale connectivity only became apparent after the large-scale network fluctuations were filtered from the timeseries. We conclude that fMRI resting state fluctuations in the visual cortex may in fact be a composite signal of different overlapping sources. Isolating the different sources could enhance correlations between BOLD and electrophysiological correlates of resting state activity.

Integration of motion responses underlying directional motion anisotropy in human early visual cortical areas.

Recent imaging studies have reported directional motion biases in human visual cortex when perceiving moving random dot patterns. It has been hypothesized that these biases occur as a result of the integration of motion detector activation along the path of motion in visual cortex. In this study we investigate the nature of such motion integration with functional MRI (fMRI) using different motion stimuli. Three types of moving random dot stimuli were presented, showing either coherent motion, motion with spatial decorrelations or motion with temporal decorrelations. The results from the coherent motion stimulus reproduced the centripetal and centrifugal directional motion biases in V1, V2 and V3 as previously reported. The temporally decorrelated motion stimulus resulted in both centripetal and centrifugal biases similar to coherent motion. In contrast, the spatially decorrelated motion stimulus resulted in small directional motion biases that were only present in parts of visual cortex coding for higher eccentricities of the visual field. In combination with previous results, these findings indicate that biased motion responses in early visual cortical areas most likely depend on the spatial integration of a simultaneously activated motion detector chain.